Clotting and Other Plasma Factors in Experimental Endotoxemia: Inhibition of Degradation by Exogenous Proteinase Inhibitors

Abstract

Endotoxemia in dogs was induced by a slow intravenous infusion of E. coli endotoxin for 2 h. Thereby, a significant decrease was observed in the plasma levels of several clotting, fibrinolysis and complement factors. The changes were studied over an experimental period of 14 h and checked for statistical significance by three-way analysis of variance. Application of the broad-spectrum proteinase inhibitor aprotinin (Trasylol®) from bovine organs clearly lowered the endotoxin-induced decline of the plasma proteins studied. By intravenous application of a specific granulocytic proteinase inhibitor (Bow-man-Birk inhibitor from soybeans), the endotoxin-induced reduction of the plasma proteins was prevented in a similar manner. It can be concluded that at least some of the pathobiochemical mechanisms observed in clotting, fibrinolysis and complement systems during endotoxemia are not only caused by a severe consumption reaction but also by unspecific proteolytic degradation due to neutral granulocytic proteinases.

Effect of Recombinant Hirudin, a Specific Inhibitor of Thrombin, on Endotoxin-induced Intravascular Coagulation and Acute Lung Injury in Pigs

“…Infusion of endotoxin (lipopolysaccharide [LPS]) into animals has been shown to cause an activation of the coagulation cascade and to cause acute lung injury characterized by pulmonary hypertension, pulmonary endothelial injury, increased pulmonary vascular permeability, and pulmonary edema (4)(5)(6)(7)(8). Serine proteases, such as thrombin, plasmin, or plasma kallikrein, generated during activation of the coagulation cascade have been shown to activate polymorphonuclear leukocytes (PMN) as well as to directly increase pulmonary vascular permeability (9)(10)(11)(12).…”

Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins.

“…Elastase is released into the circulation in acute leukemia and in septicemia (4). Several studies have indicated that the decrease in the concentration of coagulation factors seen in these conditions may be the result of direct proteolysis by leukocyte elastase (5). Leukocyte elastase also inactivates human antithrombin III (6), a2-plasmin inhibitor, and C1 inactivator (7).…”

Is There a Rationale for Using a Proteinase Inhibitor as a Standard Additive to Stored Blood?

“…On the other hand, there are data suggest ing that aprotinin may restrain the traumatic or septic activation of the various 'cascades' including the coagulation and complement systems in the circulation of the patient [10,16]. This raises the question whether apro tinin added to blood units may not exert its principal effects on events occurring in the recipient at the time of the transfusion, rather than as a stabilizer during a storage period.…”